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Here's another study involving stem cell therapy, but rather than using zinc finger nuclease technique, researchers at UC Davis engineered stem cells with three types of genes that have been found to block HIV (TRIM5, shRNA, and a TAR decoy). They plan to apply for regulatory approval to begin human trials.

ScienceDaily (May 2, 2012) — UC Davis Health System researchers are a step closer to launching human clinical trials involving the use of an innovative stem cell therapy to fight the virus that causes AIDS.

In a paper published in the May issue of the Journal of Virology, the UC Davis HIV team demonstrated both the safety and efficacy of transplanting anti-HIV stem cells into mice that represent models of infected patients. The technique, which involves replacing the immune system with stem cells engineered with a triple combination of HIV-resistant genes, proved capable of replicating a normally functioning human immune system by protecting and expanding HIV-resistant immune cells. The cells thrived and self-renewed even when challenged with an HIV viral load.

"We envision this as a potential functional cure for patients infected with HIV, giving them the ability to maintain a normal immune system through genetic resistance," said lead author Joseph Anderson, an assistant adjunct professor of internal medicine and a stem cell researcher at the UC Davis Institute for Regenerative Cures. "Ideally, it would be a one-time treatment through which stem cells express HIV-resistant genes, which in turn generate an entire HIV-resistant immune system."

To establish immunity in mice whose immune systems paralleled those of patients with HIV, Anderson and his team genetically modified human blood stem cells, which are responsible for producing the various types of immune cells in the body.Building on work that members of the team have pursued over the last decade, they developed several anti-HIV genes that were inserted into blood stem cells using standard gene-therapy techniques and viral vectors (viruses that efficiently insert the genes they carry into host cells). The resulting combination vector contained:

a human/rhesus macaque TRIM5 isoform, which disrupts HIV from uncoating in the cytoplasm

a CCR5 short hairpin RNA (shRNA), which prevents certain strains of HIV from attaching to target cells

a TAR decoy, which stops HIV genes from being expressed inside of the cell by soaking up a critical protein needed for HIV gene expression

These engineered blood stem cells, which could be differentiated into normal and functional human immune cells, were introduced into the mice. The goal was to validate whether this experimental treatment would result in an immune system that remained functional, even in the face of an HIV infection, and would halt or slow the progression toward AIDS.

The results were successful on all counts.

"After we challenged transplanted mice with live HIV, we demonstrated that the cells with HIV-resistant genes were protected from infection and survived in the face of a viral challenge, maintaining normal human CD4 levels," said Anderson. CD4+ T-cells are a type of specialized immune cell that HIV attacks and uses to make more copies of HIV.

"We actually saw an expansion of resistant cells after the viral challenge, because other cells which were not resistant were being killed off, and only the resistant cells remained, which took over the immune system and maintained normal CD4 levels," added Anderson.

The data provided from the study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validated its potential application in future human clinical trials. The team has submitted a grant application for human clinical trials and is currently seeking regulatory approval, which is necessary to move on to clinical trials.

"This research represents an important step in our fight against HIV/AIDS," said Richard Pollard, chief of infectious diseases at UC Davis and one of the study's co-authors. "Clinical trials could give us the critical information we need to determine whether our approach truly represents a functional cure for a terrible disease that has affected millions and millions of people."

The study was supported by UC Davis Health System start-up funds from the Dean's office for the Stem Cell Program and by the James B. Pendleton Charitable Trust. This work was also supported in part by the Gin and Imy Mar stem cell research fund.

There seems to be so much buzz devoted to gene therapy lately. Between this study and the Sangamo trials it appears to be all the rage. I know recently the Fred Hutch Cancer Research Center just received a huge grant from the US NIH to study gene therapy.

There is a big elephant in the room though that no one is talking about. If there ever is a gene therapy treatment for HIV it would be expected to be hugely expensive. So much so that the majority of HIV positive patients would be unable to access it.

Take Provenge, which is a cancer treatment by Dendrion. They take your blood, send it to a factory, tinker with it and do something, send it back and inject it in you. Total cost US $97,000.

When someone is on effective antiretroviral therapy, how can an insurance company, goverment agency, or individual justify the cost? You can be assured that the millions of people with HIV in the developing world of Africa, India, South America, most of Asia will not get the therapy.

I agree Bug that gene therapy is likely to be very expensive, assuming it becomes a viable treatment or a functional cure. But first, I'm just hoping that researchers can establish proof of concept that it is a pathway to a functional cure. If we can start to see documented case studies of people remaining undetectable after discontinuing their meds, that would be a great breakthrough.

From there, I'm sure researchers would work on scaling up the technique to a more cost effective level. If it could be done for $40,000 per person for example, I would think that insurance companies would cover an approach that enabled people to stop taking meds for the forseeable future since ARVs cost over $20,000 per year. Afterall, $40,000 multiplied by 1 million poz folks in the US is $40 billion. You're right that providing such a treatment to the rest of the world would be a daunting financial challenge. But then again, ARVs cost pennies on the dollar in Africa compared to here, so who's to say a new technique wouldn't also be much less expensive under a healthcare system that isn't profit driven.

Yeah, gene therapy will be expensive. But I think costs might be driven down because of improvements in manufacturing and competition.

Sangamo says they've automated the process -- that'll bring the prices down. Also, there might be a lot of companies offering stem cell therapies in the future (CalImmune, that group at Davis, etc.) This will also drive the price down.

Someone knows -- today -- if the Sangamo treatment works. In the last Sangamo/Penn study, VLs started to fall within six weeks of stopping meds. Some of the current crop of heterozygotes stopped taking their meds about two months ago (at least). In other words, if Sangamo works, there should be some people out there today who's VLs are falling and (fingers crossed) getting to UD. The one hetero guy in the prior Penn trial -- the "Trenton patient" went UD in 12 weeks. The study participants and the testers should know if this is happening right about now. How long it takes us to find out...well, I have no information there.

Heady days on the Gene Therapy front it would seem. While no doubt the treatment will be expensive as it's individualized medicine, as Cosmicdancer pointed about above the cost of ARV's can be upwards of 20k a year - and this doesn't even count the accompanying medical services which go along with being a continual patient. Insurance companies are all about the money and my feeling - my hope - is that even a one time payment of tens of thousands of dollars for a functional cure would make fiscal sense vs a lifetime of drug+ costs.

I remember reading a comment from Newt not so long ago on these pages that this is like 1990 again and perhaps good things are on the horizon. Stay tuned.

We're already seeing push-back from Europe on covering expensive drugs. Human Genome's Benlysta costs $35K/year in the US. Both UK and Germany have refused to cover it, using their cost-to-benefit analysis as justification.

Given that all the ingredients of Atripla (three separate pills) will be generic by the time gene-based treatments would be FDA approved, I can't believe the cost of generic HIV drugs will remain 20K. I think the cost will drop below 5K/year. The Indian knock-offs have already been given the green light by the US FDA to qualify for US HIV foreign aid programs (proven to be the bioequivalent). The pills can be manufactured cheaply as is demonstrated now in other countries.

I'm curious what your point is, Mitch. Are you saying that if and when a functional cure is found insurance companies will simply refuse to cover it? It's difficult to imagine the companies and investors betting millions on this technology are banking that their only customers will be folks who have the ability to pay out of pocket. I'm not trying to be antagonistic, just to understand where you're coming from.

The point is the investors are often overly optimistic when it comes to how willing the insurance companies are to cover a procedure. I think the $20K figure is way too high, based on the future price of the drugs in their generic form (although big pharma will be busy reformulating the heck out of them to extend patents... but eventually some sanity must prevail... list using three generic pills instead of one ... think Atripla.

Look at the stock charts for DNDN and HGSI. See how much they lost from the peak price due to lack of sales... in part due to the high cost of those treatments.

Perhaps a much better example would be Gleevec... where people have died because their insurance company refused to pay for the drug... or stalled long enough to be sure they were so near death that they weren't going to be around long with or without it.

I believe more than 40% of HIV drugs are provided through public assistance. Will ADAP pay 100K for someone to get access to the "cure?" Just don't know... and I can see all sorts of objections based around "moral hazard"... where the argument might be that if you give it to them, then they'll all throw away the condoms and just go for the cure if they get infected.

And It is to hard to tell for sure, but I feel that if the gene therapy was available in the $40,000 range that insurance would cover the procedure even if generic drugs are available at a much cheaper price. The reason I say this is because most insurance companies end up spending an average of $70,000 per case for individuals with cancer. If they spend such amounts for things like that... it would make sense to spend $40,000ish on gene therapy for HIV if the patient could stop taking drugs and be able to visit the doctor less.

I'm not saying Mitch is incorrect though.. it is honestly impossible to predict what these insurance companies will do, so they could very well prefer to pay for generics instead. I think it will just come down to what can save them the most money in the end and what is most efficient for their company.

The real test will be if Medicare covers it. By that time, their will be a LOT of old pozzies... assuming they last that long. A lot may just depend on what the state of Medicare is ten years from now.

Thanks, Mitch. Great points and certainly food for thought. I can see there might be some battles to be fought when this technology comes online - but isn't this always the case? I for one look forward to having that high class problem, ie getting insurance to cover an actual cure, in the not so distant future.